Retinoic Acid-related Orphan Receptor α Regulates Diurnal Rhythm and Fasting Induction of Sterol 12α-Hydroxylase in Bile Acid Synthesis

Pathak, Preeti; Li, Tiangang; Chiang, John Y.L.

doi:10.1074/jbc.m113.485987

Cited by 64 publications

(42 citation statements)

References 44 publications

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“…A comparable 4-times-a-day feeding experiment with a high cholesterol diet in rats reported results in line with ours, showing that hepatic Cyp7a1 expression remained rhythmic with regular feeding, although the timing of the peak shifted (Yamajuku et al 2009). Indeed, the core clock machinery can directly influence transcription of these genes, for example, RORα can influence the diurnal rhythm of Cyp8b1 expression (Pathak et al 2013) and DBP and REV-ERB stimulate the transcription of Cyp7a1 (Duez et al 2008;Lavery and Schibler 1993). In addition, CLOCK can directly stimulate Shp expression (Bavner et al 2005;Kerr et al 2002), by binding its E box (Oiwa et al 2007;Pan et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

Eggink

Oosterman

Goede

et al. 2017

Chronobiology International

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Desynchronization between the master clock in the brain, which is entrained by (day) light, and peripheral organ clocks, which are mainly entrained by food intake, may have negative effects on energy metabolism. Bile acid metabolism follows a clear day/night rhythm. We investigated whether in rats on a normal chow diet the daily rhythm of plasma bile acids and hepatic expression of bile acid metabolic genes is controlled by the light/dark cycle or the feeding/fasting rhythm. In addition, we investigated the effects of high caloric diets and time-restricted feeding on daily rhythms of plasma bile acids and hepatic genes involved in bile acid synthesis. In experiment 1 male Wistar rats were fed according to three different feeding paradigms: food was available ad libitum for 24 h (ad lib) or time-restricted for 10 h during the dark period (dark fed) or 10 h during the light period (light fed). To allow further metabolic phenotyping, we manipulated dietary macronutrient intake by providing rats with a chow diet, a free choice high-fat-high-sugar diet or a free choice high-fat (HF) diet. In experiment 2 rats were fed a normal chow diet, but food was either available in a 6-meals-a-day (6M) scheme or ad lib. During both experiments, we measured plasma bile acid levels and hepatic mRNA expression of genes involved in bile acid metabolism at eight different time points during 24 h. Time-restricted feeding enhanced the daily rhythm in plasma bile acid concentrations. Plasma bile acid concentrations are highest during fasting and dropped during the period of food intake with all diets. An HF-containing diet changed bile acid pool composition, but not the daily rhythmicity of plasma bile acid levels. Daily rhythms of hepatic Cyp7a1 and Cyp8b1 mRNA expression followed the hepatic molecular clock, whereas for Shp expression food intake was leading. Combining an HF diet with feeding in the light/inactive period annulled CYp7a1 and Cyp8b1 gene expression rhythms, whilst keeping that of Shp intact. In conclusion, plasma bile acids and key genes in bile acid biosynthesis are entrained by food intake as well as the hepatic molecular clock. Eating during the inactivity period induced changes in the plasma bile acid pool composition similar to those induced by HF feeding. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

Eggink

Oosterman

Goede

et al. 2017

Chronobiology International

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“…Other nuclear receptors, such as the pregnane X receptor (PXR)[20] and vitamin D receptor (VDR) [21], can also regulate BA synthesis by suppressing CYP7A1. Moreover, activation of the nuclear receptor RORα can modulate 12α-hydroxylase (CYP8B1) expression [22, 23]. …”

Section: Bile Acid Synthesis and Regulationmentioning

confidence: 99%

Bile acids, obesity, and the metabolic syndrome

Patti

2014

Best Practice & Research Clinical Gastroenterology

157

138

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Bile acids are increasingly recognized as key regulators of systemic metabolism. While bile acids have long been known to play important and direct roles in nutrient absorption, bile acids also serve as signaling molecules. Bile acid interactions with the nuclear hormone receptor farnesoid X receptor (FXR) and the membrane receptor G-protein-coupled bile acid receptor 5 (TGR5) can regulate incretin hormone and fibroblast growth factor 19 (FGF19) secretion, cholesterol metabolism, and systemic energy expenditure. Bile acid levels and distribution are altered in type 2 diabetes and increased following bariatric procedures, in parallel with reduced body weight and improved insulin sensitivity and glycemic control. Thus, modulation of bile acid levels and signaling, using bile acid binding resins, TGR5 agonists, and FXR agonists, may serve as a potent therapeutic approach for the treatment of obesity, type 2 diabetes, and other components of the metabolic syndrome in humans.

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“…36 ROR a has previously been described to induce the expression of CYP8B1 during fasting; in a study by Pathak et al a functional ROR a response element was found in the CYP8B1 promotor. 38 With this knowledge, we decided to investigate ROR a expression following dexamethasone treatment and indeed the expression of ROR a was increased. Blocking GR signaling with RU486 resulted in a reduced but not blocked expression of ROR a.…”

Section: Journal Of Clinical and Experimental Hepatologymentioning

confidence: 99%

Addition of Dexamethasone Alters the Bile Acid Composition by Inducing CYP8B1 in Primary Cultures of Human Hepatocytes

Mörk

Strom

Mode

et al. 2016

Journal of Clinical and Experimental Hepatology

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Background: Primary human hepatocytes offer the best human in vitro model for studies on human liver cell metabolism. Investigators use a variety of different media supplements and matrix biocoatings and the type of culture system used may influence the outcome. Objectives: To optimize in vitro conditions for primary human hepatocytes with regard to bile acid synthesis. Methods: Human hepatocytes were isolated and cultured on collagen type I or EHS matrigel in cell media with or without dexamethasone. The glucocorticoid receptor (GR) antagonist RU486 was used to elucidate the involvement of GR. Results: Hepatocytes cultured on EHS matrigel produced more bile acids and expressed higher levels of cholesterol 7a-hydroxylase (CYP7A1) than cells cultured on rat tail collagen. Supplementation with dexamethasone increased the formation of cholic acid (CA) and decreased chenodeoxycholic acid formation. In line with these results, the mRNA expression of sterol 12a-hydroxylase (CYP8B1) increased following dexamethasone treatment. Surprisingly, the mRNA expression of CYP7A1 and CYP27A1 was not increased to the same extent. By using the GR antagonist RU486, we concluded that CYP8B1 induction is mediated via a GR-independent pathway. An altered expression of retinoid-related orphan receptor (ROR) a and ROR a target gene Glucose-6-phosphatase (G6Pase) suggests that ROR a signaling may regulate CYP8B1 expression. Conclusion: Primary human hepatocytes have an increased bile acid synthesis rate when cultured on matrigel as compared to collagen. Exposure to glucocorticoid hormones stimulates the expression of CYP8B1, leading to an increased formation of CA and alteration of the bile acid composition. The effect is most likely mediated through a GR-independent pathway, possibly through ROR a. (J CLIN EXP HEPATOL 2016;6:87-93)

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Retinoic Acid-related Orphan Receptor α Regulates Diurnal Rhythm and Fasting Induction of Sterol 12α-Hydroxylase in Bile Acid Synthesis

Cited by 64 publications

References 44 publications

Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

Bile acids, obesity, and the metabolic syndrome

Addition of Dexamethasone Alters the Bile Acid Composition by Inducing CYP8B1 in Primary Cultures of Human Hepatocytes

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